Long-lived antibody-secreting plasma cells (PCs) are key to host defense, but PCs secreting self-reactive antibodies can cause a spectrum of autoimmune diseases. Likewise, PCs secreting allograft-specific antibodies are major mediators of chronic graft rejection. Current B cell ablation therapies target naive and memory B cells, but spare long-lived pathogenic PCs. We propose to define the role of the unfolded protein response (UPR) in the survival and function of long-lived PCs. Although the UPR is known to control the function of professional secretory cells such as PCs, how the UPR is regulated in PCs, and its role in long-term PC survival, has not been addressed. These studies will focus on the regulation of PC survival by the UPR component and endoplasmic reticulum sensor IRE1 and a novel IRE1 regulator - PDIA6. The main hypothesis to be tested is that sustained but limited IRE1 activity is required for the survival of long-lived PCs. To test this hypothesis we wil: 1) Define the role of IRE1 activity in short- and long-lived PCs, and 2) Define the role of PDIA6 activity in short- and long-lived PCs. These studies will enhance knowledge of the processes underlying the generation of long-lived PCs, and perhaps provide insights into novel strategies to constrain the survival or activity of pathogenic PCs.